The present invention is directed to the citrate salt of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene 
and pharmaceutical compositions thereof. The present invention is also directed to the various forms of the citrate salt, including its hydrate (referred to herein as Form A) and another polymorph that is an anhydrous or nearly anhydrous form (referred to herein as Form B).
The compound, 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene, binds to neuronal nicotinic acetylcholine specific receptor sites and is useful in modulating cholinergic function. This compound is useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn""s disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs, lead, arsenic, mercury), disease-induced cognitive impairment (e.g., arising from Alzheimer""s disease (senile dementia), vascular dementia, Parkinson""s disease, multiple sclerosis, AIDS, encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, Pick""s disease, Korsakoff""s syndrome and frontal and subcortical dementia), hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington""s chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, attention deficit hyperactivity disorder (ADHD), Tourette""s Syndrome, particularly, nicotine dependency, addiction and withdrawal; including use in smoking cessation therapy.
The citrate salts of this invention may also be used in a pharmaceutical composition in combination with an antidepressant such as, for example, a tricyclic antidepressant or a serotonin reuptake inhibiting antidepressant (SRI), in order to treat both the cognitive decline and depression associated with AD, PD, stroke, Huntington""s chorea or traumatic brain injury (TBI); in combination with muscarinic agonists in order to stimulate both central muscarinic and nicotinic receptors for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD, stroke, Huntington""s chorea and TBI; in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD stroke, Huntington""s chorea and TBI; or in combination with agents that slow or arrest AD such as cognition enhancers, amyloid aggregation inhibitors, secretase inhibitors, tau kinase inhibitors, neuronal anti-inflammatory agents and estrogen-like therapy.
Compounds that bind to neuronal nicotinic receptor sites, including 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene, and its hydrochloride salt, are referred to in WO 99/35131, published Jul. 15, 1999 (corresponding to U.S. Ser. Nos. 09/402,010, filed Sep. 28, 1999 and 09/514,002, filed Feb. 25, 2000). The foregoing applications, owned in common with the present application and incorporated herein by reference in their entirety, generically recite pharmaceutically acceptable acid addition salts for the compounds referred to therein.
The citrate salt of the present invention exhibits properties, including those of solid-state stability and compatibility with certain drug product formulation excipients, that render it superior to previously known salts of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene.